羟基异吲哚酮类衍生物与HIV-1整合酶的分子模拟研究

Molecular simulation study on the recognition between hydroxy isoindolin ketone derivatives and HIV-1 integrase

为了研究羟基异吲哚酮类衍生物与HIV-1整合酶识别的机制以及构象变化,采用Auto Dock对58个羟基异吲哚酮类衍生物与整合酶进行了分子对接,并对抑制HIV-1整合酶活性较好的两个化合物所形成的复合物模型分别进行了16 ns的分子动力学模拟。基于对接复合物模型分析给出了化合物与整合酶结合的主要作用力,通过分析氢键以及构象的变化,发现氨基酸残基N155与D64之间的氢键是维持整合酶催化活性所必需的DDE基序结构稳定的关键。另外,氨基酸残基Y143所在的loop区与羟基异吲哚酮类衍生物之间的疏水作用力在受体-配体识别的过程中具有重要的作用。

To discuss the conformational change and the recognition mechanism of hydroxy isoindol ketone deriv- atives with HIV-1 integrase, fifty-eight hydroxy isoindol ketone derivatives were docked to the integrase using AutoDock program. Molecular dynamics simulation with 16 ns was carried out for the two complex modes, respec- tively, in which the corresponding small molecules exhibited strong inhibition ability. Main force acting on the as- sociation of small molecules with integrase was explored based on the docking complex model. After analyzing the hydrogen-bond and conformational changes, it was found that the hydrogen-bond between N155 and D64 was the key factor maintaining the DDE motif stability. Furthermore, the hydrophobic interactions between the loop region where Y143 located and the hydroxy isoindol ketone derivatives were found to play an important role for their rec- ognition.